Claude MOLINA and Franz MARRACHE

• Anaphylaxis to Monoclonal Antibody : Cetuximab
• Eosinophil markers and corticosteroid tapering in Asthmatic patients
  
• Classical Alternaria Alternata-specific immunotherapy: Randomised study
  
• Mepolizumab and Hypereosinophilic Syndrome
  
• Geohelminthiasis and anti-IgE treatments : potential risks

Anaphylaxis to a Monoclonal Antibody : Cetuximab

Monoclonal antibodies are the therapeutic innovations of the beginning of the 21st century, successfully used in Allergy (Omalizumab) and in Oncology.

Cetuximab (Erbitux® or Mabthera® ) is a chimeric mouse-human IgG1 Monoclonal antibody_ against the Epidermal Growth Factor Receptor or EGFR. It is approved for the treatment of - colo-rectal cancers and squamous tumors of the head and neck . In some areas of the US hypersensitivity reactions have been reported with a high frequency (prevalence of 22% of cases in Tennessee and North Carolina but of 1% in the Northeast, and - an average 3%, as mentioned by drug company leaflets).

That is - why the group of Prof. Platts-Mills analyzed serum samples for anti-Cetuximab IgE antibody, particularly in individuals who had had severe allergic reactions anaphylaxis-type at the beginning of Monoclonal antibody perfusions (Cetuximab-induced anaphylaxis and IgE specific for Galactose-á-1,3-Galactose : C.H. Chung et al NEJM 2008 158 1109-1117).Then they extended their study to 76 individuals who had been on Cetuximab treatment (in Tennessee, Arkansas and North Carolina) and 72 controls in Tennessee, 49 individuals with head and neck cancers in California and 341 female control individuals in Boston. Among 76 treated individuals, 25 had hypersensitivity reactions to drug and 17 of these had Cetuximab-specific IgE antibodies, before treatment. In contrast, there was only one individual with Cetuximab-specific IgE among the remaining 51 individuals . Within the the 2nd group (control), 15 out of 72 had IgE antibodies against Cetuximab (20.8%). In the 3rd group, there were 3 Cetuximab-specific IgE+ individuals out of 49 (6.1%). Within the 4th group, there were 2 Cetuximab-specific IgE+ individuals out of 341 (0.6%). These IgE antibodies were shown to be specific for an oligosaccharide which is present on the F(ab’)2 region of Cetuximab heavy chain : Galactose-á-1,3-Galactose. They are not anti-murine protein antibodies (there is no connection with the other monoclonal antibodies such as Rituximab or Infliximab); in contrast, there is a clear correlation with antibodies against non-primate mammalian proteins : cat, dog and cow, but not against mites or pollens. The authors cannot explain the regional differences observed, but they draw attention to the need for detection of anti-Cetuximab IgE prior to treatment with this monoclonal antibody since in most subjects who had ractions to the drug, IgE antibodies were present before therapy. One may also ask whether this notion also applies to other monoclonal antibodies.

Eosinophil markers and tapering of corticosteroids in Asthmatic patients

It is known that the association of Long acting beta-agonists (LABA) to corticosteroids is more efficient than isolated drugs, and allows corticosteroid tapering. A group of Danish authors has tried to evaluate the risk associated with corticosteroid tapering, based on eosinophil markers (EM) which are regarded as signs of bronchial inflammation. 61 patients recruited in 5 Danish hospitals, and efficiently treated with doses between 750 and 1000mcg/day of Corticosteroids were randomised into 2 groups : one of the groups received the minimal dose of 500mcg Fluticasone® + 50mcg Salmeterol ®, and the other group were given 500mcg Fluticasone alone. Once Asthma was well controlled, corticosteroid doses were reduced every 6 weeks, as clinical parameters and EM were monitored, until asthma symptoms eventually reappeared or patients kept on placebo (Asthmatics able to step down from inhaled corticosteroid treatment without loss of asthma control have low serum eotaxin/CCL11 : H. J. Hoffmann et al, Clinical Respiratory Journal 2008; DOI:10.1111/j.1752-699X.2008.00054.x.)

9 patients could be kept on placebo for 6 weeks, 36 patients developed mild Asthma symptoms , 16 had severe symptoms . EM were monitored in 39 cases (blood eosinophils, EPO, ECP, and chemokines : eotaxin/CCL11, eotaxin 2/CCL24, eotaxin 3/CCL26) and Th2 cytokines : IL1-â, IL-4, IL-5, TNF-á, INF-ã. Among the EM, eotaxin/CCL 11 seemed to be the most discriminating variable : patients who were able to be kept on placebo without developing severe symptoms had noticeably lower eotaxin levels than those who developed moderate or severe Asthma.

Thus, eosinophilic chemokines are, according to the authors, a useful guide for the tapering of corticosteroids in Asthmatic patients.

Alternaria Alternata-specific classical immunotherapy : Randomised study

Fungi are, after house dust mites and pollens, the 3rd most important cause of respiratory allergies. Among allergy-inducing fungi, besides Aspergillus and Penicillium, Cladosporium is the most frequent one in the North of Europe whereas Alternaria seems to predominate in Mediterranean regions. In any case, desensitisation to fungi does not have a great reputation of efficacy or tolerance induction. Spanish authors carried out a treatment with a metabolic extract -previously standardised and controlled, (by skin prick testing and immuno-enzymology) in a randomised, double blind, placebo-controlled study, involving 28 patients between 7 and 29 years of age (of which 14 were controls) who had Rhinitis with or without associated Asthma and were monosensitised to Alternaria . (Double-blind, placebo-controlled study of Alternaria alternata immunotherapy: Clinical efficacy and safety Ana I. Tabar et al Pediatric Allergy and Immunology, February 2008 Volume 19 Issue 1 Page 76-81).

The protocol followed was a classical one, performed in accordance with the criteria of the EAACI. : one injection per week of a progressively higher dose of allergen extract until a maintenance dose was achieved (or the maximal tolerated dose), then once monthly for 6 to 12 months ( 1670 BE Units, corresponding to 0.167mg of lyophilised extract containing 0.1µg Alt a 1 ).

23 patients were able to complete the treatment with only 2 developing minimal side effects such as cutaneous pruritus.
It took 6 months to observe a significant improvement in all respiratory symptoms (measured clinically and with daily clinical scores) in the treated group. FEV1 was also significantly increased, but not in the placebo group. Asthma severity was decreased only in the treated group, but the symptoms of rhinitis or rhino-conjunctivitis were decreased in both after one year of treatment .

Thus, in this randomised study involving a limited number of patients and including a regular count of Alternaria spores in the environment of both randomised groups of patients, desensitisation, which was well tolerated, was efficacious at decreasing respiratory symptoms and function, but its effects were less clear upon rhino-conjunctivitis .

It is nevertheless a kind of rehabilitation of specific immunotherapy at a time where its efficacy is doubtful, even among allergists.

Mepolizumab and hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) includes a group of illnesses that are associated with blood eosinophilia > 1000 eosinophils/ml and eosinophil tissue influx into affected organs. Manifestations may be variable and may include respiratory, cardiac, gastro-intestinal, muscle and skeletal, cutaneous and neurological symptoms. Efficacy of corticosteroids in most HES cases is acknowledged, but is associated with side effects that may involve an important morbidity.

Taking into consideration the involvement of interleukin-5 (IL-5) in the development of eosinophils from their bone marrow precursors, as well as its role in the maturation, differentiation, mobilisation, activation and survival of this cell type, it was thus logical to ask whether using a humanised anti-IL-5 monoclonal antibody might be associated with corticosteroid-sparing effects in HES.

An international, multicentre, double blind study was performed between March 2004 and March 2006 by the Mepolizumab Group. NEJM published the results in a recent article (M.E. Rothenberg et al , Treatment of Patients with theEosinophilic Syndrome with Mepolizumab. NEJM march 20, 2008 vol. 358 no. 12)

Out of 107 recruited patients who were negative for the FIP1L1–PDGFRA fusion gene (which allows exclusion of cases of myeloproliferative HES, which usually require treatment by Imatinib) 87 individuals were selected and randomised into 2 goups : Mepolizumab group (MG) and placebo group (PG). All selected patients were clinically stabilised on a daily dose of 20 to 60 mg prednisone or prednisone equivalent, and their blood eosinophilia was < 1000/ml. Mepolizumab at a dose of 750mg or placebo were given as intravenous perfusion every 4 weeks for the duration of the study (36 weeks). The main objective of the study was to decrease prednisone or prednisone- equivalent to 10mg/day or even less for 8 consecutive weeks or even longer.

Within the MG group, 36/43 participants (84%) were able to achieve the protocol until its conclusion whereas in the PG only 36% of patients were able to do so. The clearly more frequent patient dropouts within the PG group were particularly linked to the re-occurrence of symptoms due to the decrease in corticosteroid dose.

The objective was attained in 84% of patients of the MG group versus 43% within the PG group. A reduction in corticosteroid doses to < 10 mg/day without destabilisation of the clinical status or an increase in eosinophilia was possible for a period of 8 weeks in almost all MG patients whereas it was only possible in 41% of PG patients.

Severe reactions, not associated with the drug, were observed with a similar frequency in both groups (5 to 7 patients). Drug-related side-effects were varied, not severe and were not more frequent in any of the groups.

In conclusion, Mepolizumab, which targets eosinophils, seems to allow a steroid-sparing effect in HES patients that are negative for the FIP1L1–PDGFRA fusion gene.

Geohelminthiases and Omalizumab : potential risks

If the role of IgE antibodies in anti-parasite defense is not denied, their place deserves to be clarified as mentioned byP.J. Cooper et al, (Geohelminth infections: a review of the role of IgE and assessment of potential risks of anti-IgE treatment, Allergy 2008: 63: 409–417).

In order to try and assess the potential role of IgE responses against helminths in humans and the possible risk associated with treatment by Omalizumab, the authors cite the study carried out by Cruz AA et al (Safety of antiimmunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy2007;37:197–20).

In this study, 137 Brazilian patients, with a high risk of parasitic infection, aged between 12 and 30 years, with asthma or perennial allergic rhinitis were selected. Before the beginning of the study, an adequate anti-helminthic treatment was given to the patients in order to free them from any parasitic infection. In this double blind, placebo-controlled, 52 week-long study, participants included in the active group were given one sub-cutaneous injection of Omalizumab every 2 to 4 weeks.

At the end of the study, the rate of parasitic infections was practically identical in both groups. There was a slightly higher, but not significant, morbidity within the actively treated group, with a more relevant propensity of these individuals for re-infection.

Overall, risks that allergic patients on Omalizumab treatment face depend upon the type of population, the degree of exposure and the nature of the parasitic infection :

- negligible risk for populations who live in the European Union or the US, in case of minimal exposure, and very low risk in case of short exposure, as when on holidays, for instance;

- low risk for prolonged stays such as those involving volunteers that work in missions abroad (risk that depends upon the nature of the parasite);

- low to moderate risk for migrants originating from endemic areas;

- in contrast, increased vigilance is necessary for individuals having had previous infection with Strongyloides, given the ubiquitous feature of this parasite.

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